PROJECT 1 : Molecular Genetics Chronic lymphocytic leukemia (CLL), an incurable disease that affects individuals over 50 years of age, is the most common leukemia in the Western World. At present, the clinical approach to the treatment of CLL is wait and watch because in most cases the disease is indolent, often for long periods of time, although with time it may transform into an aggressive disease. Thus, it may be counterproductive to treat a disease that may remain indolent for long periods of time with aggressive chemo/immunotherapy. On the contrary, the aggressive form of CLL, that involves approximately 20-30% of patients, is a malignant disease with poor prognosis that should be treated promptly and aggressively. During the past few years, with the support of this grant and of interactions and collaborations with investigators of the other projects, we have discovered the fundamental genetic changes responsible for the indolent and aggressive forms of CLL. We were. also able to develop mouse models for both the aggressive and indolent forms of CLL. Recently we have compared the microRNA expression profiles in samples obtained from CLL patients that have remained indolent for many years, to samples obtained from CLL patients that were indolent but became aggressive with time and we have identified specific changes in microRNA expression that correlate with the malignant progression. In this renewal application, we intend unravel the fundamental changes that convert an indolent to an aggressive disease by the following aims: AIM #1 Detection of the genome-wide microRNA alterations during the progression of CLL AIM #2 Studies of the molecular networks controlled by the altered microRNAs AIM #3 Identification of the factors promoting microRNAs dysregulation during the progression of CLL We also plan to exploit the mouse models we have developed with this grant support to unravel the mechanisms involved in tumor progression, thus facilitating an understanding of the progression of human CLL.